Lymphocyte Activation Gene-3, or LAG3 (also known as CD223), is a member of the immunoglobulin supergene family and is structurally and genetically related to CD4. LAG3 is not expressed on resting peripheral blood lymphocytes but is expressed on activated T cells and NK cells. LAG3 is a membrane protein encoded by a gene located on the distal part of the short arm of chromosome 12, near the CD4 gene, suggesting that the LAG3 gene may have evolved through gene duplication (Triebel et al. (1990) J. Exp. Med. 171:1393-1405).
Similar to CD4, LAG3 has been demonstrated to interact with MHC Class II molecules but, unlike CD4, LAG3 does not interact with the human immunodeficiency virus gp120 protein (Baixeras et al. (1992) J. Exp. Med. 176:327-337). Studies using a soluble LAG3 immunoglobulin fusion protein (sLAG3Ig) demonstrated direct and specific binding of LAG3 to MHC class II on the cell surface (Huard et al. (1996) Eur. J. Immunol. 26:1180-1186).
In in vitro studies of antigen-specific T cell responses, the addition of anti-LAG3 antibodies led to increased T cell proliferation, higher expression of activation antigens such as CD25, and higher concentrations of cytokines such as interferon-gamma and interleukin-4, supporting a role for the LAG3/MHC class II interaction in down-regulating antigen-dependent stimulation of CD4+ T lymphocytes (Huard et al. (1994) Eur. J. Immunol. 24:3216-3221). The intra-cytoplasmic region of LAG3 has been demonstrated to interact with a protein termed LAP, which is thought to be a signal transduction molecule involved in the downregulation of the CD3/TCR activation pathway (Iouzalen et al. (2001) Eur. J. Immunol. 31:2885-2891). Furthermore, CD4+CD25+ regulatory T cells (Treg) have been shown to express LAG3 upon activation and antibodies to LAG3 inhibit suppression by induced Treg cells, both in vitro and in vivo, suggesting that LAG3 contributes to the suppressor activity of Treg cells (Huang, C. et al. (2004) Immunity 21:503-513). Still further, LAG3 has been shown to negatively regulate T cell homeostasis by regulatory T cells in both T cell-dependent and independent mechanisms (Workman and Vignali (2005) J. Immunol. 174:688-695).
In certain circumstances, LAG3 also has been shown to have immunostimulatory effects. For example, LAG3 transfected tumor cells transplanted into syngeneic mice showed growth reduction or complete regression as compared to untransfected tumor cells, suggesting that LAG3 expression on the tumor cells stimulated an anti-tumor response by triggering antigen LAG3 presenting cells via MHC class II molecules (Prigent et al. (1999) Eur. J. Immunol. 29:3867-3876). Additionally, soluble LAG3 Ig fusion protein has been shown to stimulate both humoral and cellular immune responses when administered to mice together with an antigen, indicating that soluble LAG3Ig can function as a vaccine adjuvant (El Mir and Triebel (2000) J. Immunol. 164:5583-5589). Furthermore, soluble human LAG3Ig has been shown to amplify in vitro generation of type I tumor-specific immunity (Casati et al. (2006) Cancer Res. 66:4450-4460). The functional activity of LAG3 is reviewed further in Triebel (2003) Trends Immunol. 24:619-622. In view of the above, additional agents for modulating the activity of LAG3 are of interest.